N2'-Branched Acyclic Nucleoside Phosphonates Containing 9-Deazahypoxanthine as Inhibitors of Plasmodium falciparum 6-Oxopurine Phosphoribosyltransferase

0573369 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Vaňková, Karolína - Keough, D. T. - Hocková, Dana - Guddat, L. W. - Janeba, Zlatko
N2'-Branched Acyclic Nucleoside Phosphonates Containing 9-Deazahypoxanthine as Inhibitors of Plasmodium falciparum 6-Oxopurine Phosphoribosyltransferase.
ChemMedChem. Roč. 18, č. 15 (2023), č. článku e202300211. ISSN 1860-7179. E-ISSN 1860-7187
Grant CEP: GA ČR(CZ) GA19-07707S
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * inhibitors * hypoxanthine-guanine-(xanthine) phosphoribosyltransferase * malaria * Plasmodium falciparum
Obor OECD: Organic chemistry
Impakt faktor: 3.4, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1002/cmdc.202300211

Twelve N2'-branched acyclic nucleoside phosphonates and bisphosphonates were synthesized as potential inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT), the key enzyme in the purine salvage pathway for production of purine nucleotides. The chemical structures were designed with the aim to study selectivity of the inhibitors for PfHGXPRT over human HGPRT. The newly prepared compounds contain 9-deazahypoxanthine connected to a phosphonate group via a five-atom-linker bearing a nitrogen atom (N2') as a branching point. All compounds, with the additional phosphonate group(s) in the second aliphatic linker attached to N2' atom, were low micromolar inhibitors of PfHGXPRT with low to modest selectivity for the parasite enzyme over human HGPRT. The effect of the addition of different chemical groups/linkers to N2' atom on the inhibition constants and selectivity is discussed.
Trvalý link: https://hdl.handle.net/11104/0343833